POS1311 HETEROZYGOUS IFIH-1 and DDX58 VARIANTS DETECTED IN CHILDREN WITH IMMUNO-MEDIATED DISEASES
Authors: R. Raupov, E. Suspitsin, R. Mulkidzhan, M. Kostik
Journal: Annals of the Rheumatic Diseases (2022)

Background IFIH1 gene codes for the MDA5 protein participating in interferon I signaling pathway, which is important in the innate immune response [1]. IFIH1 polymorphisms are associated with a spectrum of autoimmune disease [2]. Rare IFIH1 gene defects have been found in patients with Aicardi- Goutières syndrome-7, Singleton-Merten syndrome, and MDA-5 immunodeficiency. All these conditions are characterized by upregulation of interferon signaling [3]. DDX58 encodes RIG-I receptor that is responsible for the recognizing of single- and double-stranded viral RNA. Mutation of DDX58 was described in Singleton-Merten syndrome [4]. Objectives to describe clinical characteristics of patients with rare IFIH1 and DDX58 variants detected by clinical exome sequencing. Methods 8 patients (5 girls and 3 boys) having rare IFIH1 and DDX58 variants (MAF less than 0.005) were found in heterozygous state among the patients who underwent genetic testing in our hospital in 2019-2021. Clinical manifestations, laboratory parameters, IFN I score values and treatment options were analyzed. Results 3 patients (#3, #6, #7) had undifferentiated systemic autoinflammatory syndromes, while others were presented with SLE, SLE-like disease, JDM and PFAPA syndrome. All of them had elevated IFN-I score and skin rash. IFIH-1 variants were in 5 patients (#1-5); 3 patients carried the same c.1879G&gt;T polymorphic variant. Patient #6-8 have VUS DDX58 variants. All the alleles were in heterozygous state. Detailed information is presented in Table 1. Table 1. # Genetic variants MAF IFN-score Diagnosis Manifestation Treatment 1 IFIH1 c.1879G&gt;T (p.E627X) 0.003 11.3 SLE Fever, photosensitivity, pancytopenia, thrombosis CS, RTX, MMF 2 IFIH1 c.1879G&gt;T (p.E627X) 0.003 2.95 PFAPA Fever, pharyngitis, stomatitis, adenitis CS in flares 3 IFIH1 c.1558A&gt;G p.T520A 0.00009 5.52 uSAID Fever, pancytopenia, petechias, panniculitis, hepatomegaly, inflammation CS, CsA, TOC, TOF 4 IFIH1: c.1784G&gt;A (p.R595H) 0.0001 29.0 JDM Gottron’s papules, periorbital erythema, muscle weakness, osteoarthritis CS, CYC, IVIG, MTX 5 IFIH1 c.1879G&gt;T (p.E627X) 0.003 20.2 SLE-like disease Face erythema, skin thickening topical tacrolimus 6 DDX58 c1061A&gt;G (p.N354S) 0.00007 2.13 uSAID Recurrent pericarditis CS 7 DDX58 c109G&gt;A (p.E37K) 0.000008 n/a uSAID Fever, livedo racemose, inflammation NSAIDS 8 DDX58 c.2587_2590dup (p.Cys864fs) 0.0006 21.0 SLE Skin, mucous, joints, kidney involvement, pancytopenia CS, RTX Abbreviations: MAF- minor allele frequency; SLE- systemic lupus erythematosus; uSAID- undifferentiated systemic autoinflammatory syndrome; JDM- juvenile dermatomyositis; CS- corticosteroids; RTX- rituximab; CYC- cyclophosphamide; MTX- methotrexate; IVIG- intravenous immunoglobulin; MMF- mycophenolate mofetil; CsA- cyclosporine A; TOF- tofacitinib. Conclusion while rare IFIH1 and DDX58 variants have been repeatedly detected in children with clinically heterogeneous immune-mediated diseases, it is unclear whether these alleles have casual role. Functional testing and collection of patients with the same gene variants are required. References [1] https://medlineplus.gov/genetics/gene/ifih1/#resources [2]Zervou M, Andreou A, Goulielmos G, et al AB0004 THE ASSOCIATION OF THE RARE RS35667974 IFIH1 GENE POLYMORPHISM WITH SIX AUTOIMMUNE DISEASES: STRUCTURAL BIOLOGICAL INSIGHTS Annals of the Rheumatic Diseases 2021;80:1037 [3]Rice, G. I., Park, S., Gavazzi et al. (2020). Genetic and phenotypic spectrum associated with IFIH1 gain-of-function. Human Mutation. doi:10.1002/humu.23975 [4]Jang MA, Kim EK, Now H, et al. Mutations in DDX58, which encodes RIG-I, cause atypical Singleton-Merten syndrome. Am J Hum Genet. 2015;96(2):266-274. doi:10.1016/j.ajhg.2014.11.019 Acknowledgements This work was supported by the RSF grant № 20-45-01005 Disclosure of Interests None declared